The clinical characteristics and natural history of FSS distinguish it from other forms of arthrogryposis, yet FSS is frequently misdiagnosed. Children with FSS require considerable nutritional, surgical, and rehabilitative intervention. Such intensive therapeutic demands differ substantially from most other congenital contracture syndromes. These findings underscore the necessity of making an accurate diagnosis.

The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive malformation syndrome associated with increased levels of 7-dehydro-cholesterol (7-DHC) and a defect of cholesterol biosynthesis at the level of 3 beta-hydroxy-steroid-delta7-reductase (7-DHC reductase). Because rats exposed to inhibitors of 7-DHC reductase during development have a high frequency of holoprosencephaly (HPE) [Roux et al., 1979], we have undertaken a search for biochemical evidence of RSH/SLOS and other possible defects of sterol metabolism among patients with various forms of HPE. We describe 4 patients, one with semilobar HPE and three others with less complete forms of the HPE sequence, in whom we have made a biochemical diagnosis of RSH/SLOS. The clinical and biochemical spectrum of these and other patients with RSH/SLOS suggests a role of abnormal sterol metabolism in the pathogenesis of their malformations. The association of HPE and RSH/SLOS is discussed in light of the recent discoveries that mutations in the embryonic patterning gene, Sonic Hedgehog (SHH), can cause HPE in humans and that the sonic hedgehog protein product undergoes autoproteolysis to form a cholesterol-modified active product. These clinical, biochemical, and molecular studies suggest that HPE and other malformations in SLOS may be caused by incomplete or abnormal modification of the sonic hedgehog protein and, possible, other patterning proteins of the hedgehog class, a hypothesis testable in somatic cell systems.

A multistate Centers for Disease Control and Prevention (CDC) study was designed to investigate the etiology of congenital hearing loss in infants ascertained through state-mandated hearing screening or early hearing loss detection and intervention (EHDI) programs. At least 50% of permanent childhood-onset hearing loss is due to genetic causes, and approximately 20% of all infants with congenital hearing loss have mutations in the GJB2 gene. Another 1% of childhood hearing loss is due to mitochondrial DNA (mtDNA) mutations. The specific aims of this study are to 1) classify the etiology of congenital hearing loss in infants by doing prospective genetic evaluations of all newborns with permanent hearing loss from defined geographic areas, 2) determine the frequency of mutations in GJB2 and two common mitochondrial mutations in these populations, and 3) establish a model infrastructure linking genetic services to statewide EHDI programs. As of April 2003, Utah is the only center evaluating patients. Study subjects identified through the Utah Department of Health EHDI program are contacted by letter and offered a comprehensive medical genetics evaluation with DNA testing for GJB2 and mitochondrial mutations A1555G and A7445G. To date, 25 probands and their immediate family members have been evaluated. We have identified 20 cases with nonsyndromic hearing loss (7 multiplex and 13 simplex), 4 with syndromic hearing loss, and 1 with presumed cytomegalovirus (CMV)-induced hearing loss. Six of 19 (32%) nonsyndromic cases with sensorineural hearing loss have mutations of one or both alleles of the GJB2 gene, and 21% are homozygous or compound heterozygotes for the 35delG mutation. No A1555G or A7445G mtDNA mutations have been found. Data reported to date include only children born in Utah, but EHDI programs in Hawaii, Rhode Island, and designated areas of Georgia have begun enrolling children in what is now a multistate collaborative study. This is the first comprehensive investigation to determine the etiology of hearing loss from populations ascertained through EHDI programs. The results of this study will facilitate the incorporation of genetic services into EHDI programs. ß

We report on a 12-year-old boy who presented with delayed development and CNS dysmyelination. Genetic studies showed a normal 46,XY karyotype by routine cytogenetic analysis, and 46,XY.ish del(18)(q23)(D18Z1+, MBP-) by FISH using a locus-specific probe for the MBP gene (18q23). Though the patient appeared to have normal chromosome 18s by repeated high resolution banding analysis, his clinical features were suggestive of a deletion of 18q. These included hearing loss secondary to stenosis of the external auditory canals, abnormal facial features, and foot deformities. FISH studies with genomic probes from 18q22.3 to 18qter confirmed a cryptic deletion which encompassed the MBP gene. In an attempt to further characterize the deletion, whole genome screening was conducted using array based comparative genomic hybridization (array CGH) analysis. The array CGH data not only confirmed a cryptic deletion in the 18q22.3 to 18qter region of approximately 7 Mb, it also showed a previously undetected 3.7 Mb gain of 4q material. FISH studies demonstrated that the gained 4q material was translocated distal to the 18qter deletion breakpoint. The 18q deletion contains, in addition to MBP, other known genes including CYB5, ZNF236, GALR1, and NFATC1, while the gained 4q material includes the genes FACL1 and 2, KLKB1, F11 and MTNR1A. The use of these combined methodologies has resulted in the first reported case in which array CGH has been used to characterize a congenital chromosomal abnormality, highlighting the need for innovative molecular cytogenetic techniques in the diagnosis of patients with idiopathic neurological abnormalities.